Dataset Information

Sacubitril/Valsartan Improves Left Ventricular Function in Chronic Pressure Overload Independent of Intact Cyclic Guanosine Monophosphate-dependent Protein Kinase I Alpha Signaling.

ABSTRACT:

Background

Combined angiotensin receptor/neprilysin inhibition with sacubitril/valsartan (Sac/Val) has emerged as a therapy for heart failure. The presumed mechanism of benefit is through prevention of natriuretic peptide degradation, leading to increased cyclic guanosine monophosphate (cGMP)-dependent protein kinase (PKG) signaling. However, the specific requirement of PKG for Sac/Val effects remains untested.

Methods and results

We examined Sac/Val treatment in mice with mutation of the cGMP-dependent protein kinase I (PKGI)α leucine zipper domain, which is required for cGMP-PKGIα antiremodeling actions in vivo. Wild-type (WT) or PKG leucine zipper mutant (LZM) mice were exposed to 56-day left ventricular (LV) pressure overload by moderate (26G) transaortic constriction (TAC). At day 14 after TAC, mice were randomized to vehicle or Sac/Val by oral gavage. TAC induced the same degree of LV pressure overload in WT and LZM mice, which was not affected by Sac/Val. Although LZM mice, but not WT, developed LV dilation after TAC, Sac/Val improved cardiac hypertrophy and LV fractional shortening to the same degree in both the WT and LZM TAC mice.

Conclusion

These findings indicate the beneficial effects of Sac/Val on LV structure and function in moderate pressure overload. The unexpected finding that PKGIα mutation does not abolish the Sac/Val effects on cardiac hypertrophy and on LV function suggests that signaling other than natriuretic peptide- cGMP-PKG mediates the therapeutic benefits of neprilysin inhibition in heart failure.

SUBMITTER: Tam K

PROVIDER: S-EPMC7529795 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Publications

Sacubitril/Valsartan Improves Left Ventricular Function in Chronic Pressure Overload Independent of Intact Cyclic Guanosine Monophosphate-dependent Protein Kinase I Alpha Signaling.

Tam Kelly K Richards Daniel A DA Aronovitz Mark J MJ Martin Gregory L GL Pande Suchita S Jaffe Iris Z IZ Blanton Robert M RM

Journal of cardiac failure 20200525 9

<h4>Background</h4>Combined angiotensin receptor/neprilysin inhibition with sacubitril/valsartan (Sac/Val) has emerged as a therapy for heart failure. The presumed mechanism of benefit is through prevention of natriuretic peptide degradation, leading to increased cyclic guanosine monophosphate (cGMP)-dependent protein kinase (PKG) signaling. However, the specific requirement of PKG for Sac/Val effects remains untested.<h4>Methods and results</h4>We examined Sac/Val treatment in mice with mutatio ...[more]

PMID: 32464187

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Project description:AimsOestrogen exerts beneficial cardiovascular effects by binding to specific receptors on various cells to activate nuclear and non-nuclear actions. Oestrogen receptor α (ERα) non-nuclear signalling confers protection against heart failure remodelling, involving myocardial cyclic guanosine monophosphate (cGMP)-cGMP-dependent protein kinase G (PKG) activation; however, its tissue-specific role remains elusive. Herein, we examine the cell type-specific role of ERα non-nuclear signalling in oestrogen-conferred protection against heart failure.Methods and resultsWe first assessed the tissue-specific impacts of ERα on the cardiac benefits derived from oestrogen, utilizing endothelial ERα deletion (ERαf/f/Tie2Cre+) and myocyte ERα deletion (ERαf/f/αMHCCre+) female mice. Female mice were ovariectomized and the effect of estradiol (E2) was assessed in hearts exposed to 3 weeks of pressure overload [transverse aortic constriction (TAC)]. E2 failed to improve cardiac function in ERαf/f/Tie2Cre+ TAC hearts but provided benefits in ERαf/f/αMHCCre+ TAC hearts, indicating that endothelial ERα is essential. We next assessed the role of non-nuclear signalling in endothelial cells (ECs), employing animals with endothelial-specific inactivation of ERα non-nuclear signalling (ERαKI/KI/Tie2Cre+). Female ovariectomized mice were supplemented with E2 and subjected to 3-week TAC. ERαKI/KI/Tie2Cre+TAC hearts revealed exacerbated cardiac dysfunction and reduced myocardial PKG activity as compared to littermate TAC hearts, which were associated with attenuated myocardial induction of vascular endothelial growth factor (VEGF) and angiogenesis as assessed by CD31-stained capillary density. This phenotype of ERαKI/KI/Tie2Cre+was rescued by myocardial PKG activation from chronic treatment with a soluble guanylate cyclase (sGC) stimulator. We performed co-culture experiments to determine endothelial-cardiomyocyte interactions. VEGF induction by E2 in cardiac myocytes required a co-existence of intact endothelial ERα signalling in a nitric oxide synthase-dependent manner. On the other hand, VEGF was induced in myocytes directly with an sGC stimulator in the absence of ECs.ConclusionAn endothelial oestrogen-myocardial cGMP axis stimulates angiogenic response and improves cardiac performance during pressure overload.

Project description:BackgroundThe ratio of ucGMP (urinary cyclic guanosine monophosphate) to BNP (B-type natriuretic peptide) is thought to reflect the responsiveness of tissues to natriuretic peptides.MethodsWe examined the relationship between ucGMP/BNP ratio and clinical outcomes, the effect of sacubitril/valsartan, compared with enalapril, on the ucGMP/BNP ratio, and the efficacy of sacubitril/valsartan on clinical outcomes according to baseline ucGMP/BNP ratio in PARADIGM-HF trial (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure). ucGMP/BNP ratio was available at baseline (N=2031), 1 month (N=1959), and 8 months after randomization (N=1746). The primary outcome was a composite of heart failure hospitalization or cardiovascular death.ResultsCompared with the lowest tertile of baseline ucGMP/BNP ratio, patients in the higher tertiles had a lower risk of the primary outcome (tertile 1, reference; tertile 2, hazard ratio 0.57 [95% CI, 0.45-0.71]; tertile 3, hazard ratio, 0.54 [0.43-0.67]). Compared with baseline, the ucGMP/BNP ratio at 1 month and 8 months after randomization was higher with sacubitril/valsartan than with enalapril: ratio of geometric mean ratios at 1 month, 1.38 (95% CI, 1.27-1.51) and 8 months, 1.32 (95% CI, 1.20-1.45), and this difference was consistent across tertiles of ucGMP/BNP ratio at baseline (Pinteraction=0.19 and 0.91, respectively). The effect of sacubitril/valsartan, compared with enalapril, was consistent across tertiles of ucGMP/BNP ratio at baseline for all outcomes (Pinteraction ≥0.31).ConclusionsIn patients with heart failure and reduced ejection fraction, higher ucGMP/BNP ratio was associated with better outcomes. Sacubitril/valsartan increased the ucGMP/BNP ratio, compared with enalapril, and the effect of sacubitril/valsartan on clinical outcomes was not modified by baseline ucGMP/BNP ratio.RegistrationURL: https://www.Clinicaltrialsgov; Unique Identifier: NCT01035255.

Dataset Information

Sacubitril/Valsartan Improves Left Ventricular Function in Chronic Pressure Overload Independent of Intact Cyclic Guanosine Monophosphate-dependent Protein Kinase I Alpha Signaling.

Background

Methods and results

Conclusion

Publications

Sacubitril/Valsartan Improves Left Ventricular Function in Chronic Pressure Overload Independent of Intact Cyclic Guanosine Monophosphate-dependent Protein Kinase I Alpha Signaling.

Similar Datasets

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